Neural Control of Choroidal Function

脉络膜功能的神经控制

• 批准号: 10716937
• 负责人: Paul Douglas Gamlin
• 金额: $ 54.57万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716937
• 关键词: Address; Affect; Age related macular degeneration; Anatomy; Angiography; Autonomic Pathways; Autopsy; Birds; Blood Pressure; Blood capillaries; Blood flow; Bruch' s basal membrane structure; Cell Nucleus; Chemicals; Choroid; Compensation; Darkness; Diabetic Retinopathy; Disease; Electrophysiology (science); Electroretinography; Eye; Eye diseases; Future; Ganglia; Goals; Health; Histology; Hour; Human; Injections; Insulin-Dependent Diabetes Mellitus; Investigation; Label; Laser-Doppler Flowmetry; Lasers; Lesion; Life; Light; Lighting; Location; Long-Term Effects; Macular degeneration; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Modeling; Motor; Motor Neurons; Neuroanatomy; Neurons; Nucleus solitarius; Optical Coherence Tomography; Parasympathetic Nervous System; Pathway interactions; Perfusion; Photic Stimulation; Photoreceptors; Physiology; Primates; Rabies; Rabies virus; Reporting; Rest; Retina; Retinal Ganglion Cells; Rodent; Role; Serous; Structure of ciliary ganglion; Structure of retinal pigment epithelium; Synapses; Thick; Time; Tracer; Vascular blood supply; Vertebrate Photoreceptors; Vision; Visual Fields; circadian; electrical microstimulation; experimental study; fovea centralis; improved; inflammatory marker; intravitreal injection; luminance; macula; melanopsin; nerve supply; neural; neural circuit; neuroregulation; nonhuman primate; paraventricular nucleus; pharmacologic; response; suprachiasmatic nucleus; visual stimulus

PROJECT SUMMARY In primates, including humans, the macula and especially the fovea, is critical for high-acuity vision. The metabolic needs of the fovea and macula are primarily met by the choriocapillaris, the capillary network of the choroid located immediately behind Bruch’s membrane. There is considerable evidence that compromised choroidal perfusion contributes to many eye diseases, such as age-related macular degeneration and diabetic retinopathy, that affect these retinal regions. Importantly, choroidal blood flow is substantially controlled by inputs from the parasympathetic nervous system. However, the parasympathetic circuitry controlling the choroidal vasculature in primates is very poorly understood. The precise locations of the pre- and postganglionic parasympathetic motoneurons supplying the choroid, as well as their premotor inputs have not been established, nor have the functional roles of these neurons been fully defined. Therefore, the overall goal of this proposal is to determine the location and function of the parasympathetic circuits controlling the choroidal vasculature in non-human primates. We propose to perform neuroanatomical, electrophysiological, and pharmacological experiments to address these questions. Specifically, in Aim 1, we will use retrograde tracers, both conventional and trans-synaptic, to identify the motor and premotor circuitry controlling the parasympathetic innervation of the choroid. In the functional part of the study, we will use infrared (IR) laser doppler flowmetry, IR laser speckle flowgraphy (LSFG), and optical coherence tomography (OCT)/OCT angiography (OCTA) to measure the choroidal vasculature. Specifically, in Aim 2, we will study the effects on the choroidal vasculature of modulating preganglionic motoneuron activity by electrical microstimulation and of modulating retinal activity by light. In Aim 3A, we hypothesize that pharmacological inactivation of preganglionic motoneurons reduces overall choroidal blood flow and thickness in darkness, reduces choroidal blood flow compensation for changes in blood pressure, and eliminates luminance induced changes in the choroidal vasculature. In Aim 3B, we hypothesize that electrolytic or chemical lesions of preganglionic motoneurons will result in reduced choroidal blood flow. In the long term, we hypothesize that the retina will show evidence of outer segment loss and inflammatory markers. We will non-invasively assess retina, retinal pigment epithelium, and choroid health in life by OCT/OCTA, LSFG, and electroretinogram (ERG)/multifocal ERG. We will further assess retinal health postmortem by retinal histology. The proposed experiments will constitute the first extensive and systematic investigation of the circuitry and role of the parasympathetic, preganglionic neurons controlling blood flow in the choroidal vasculature of a primate. These results will set the stage for future studies in which this circuitry is modulated in order to improve the survival of central vision in human macular degeneration.

项目摘要 在包括人类在内的主要中，黄斑，尤其是中央凹者对于高敏感视力至关重要。这 中央凹和黄斑的代谢需求是由Choriocapillaris主要满足的， 脉络膜位于布鲁克膜的后面。有大量证据表明 脉络膜灌注会导致许多眼部疾病，例如与年龄有关的黄斑变性和糖尿病 视网膜病，影响这些视网膜区域。重要的是，脉络膜血流基本控制 副交感神经系统的输入。但是，控制了 私人的脉络膜脉管系统非常了解。前和前的精确位置 供应脉络膜及其前输入的伴流气管副交感神经元尚未 建立了这些神经元的功能作用，也没有充分定义。因此，总体目标 该建议的是确定控制副交感神经的位置和功能 非人类隐私的脉络膜脉管系统。我们建议执行神经解剖学，电生理学， 和制药实验以解决这些问题。具体来说，在AIM 1中，我们将使用逆行 传统和反式突触的示踪剂，以识别控制电动机和前运动电路 脉络膜的副交感神经。在研究的功能部分，我们将使用红外线（IR）激光器 多普勒流量金属，IR激光斑点流量计（LSFG）和光学相干断层扫描（OCT）/OCT 血管造影（八八）测量脉络膜脉管系统。具体来说，在AIM 2中，我们将研究对 通过电微刺激和 通过光调节视网膜活动。在AIM 3A中，我们假设该药物的灭活 gangionic运动神经元减少了黑暗中的整体脉络膜血流和厚度，可减少脉络膜 血流的血流赔偿是血压变化的，并消除了亮度引起的变化 脉络膜脉管系统。在AIM 3B中，我们假设怀孕的电解或化学病变 运动神经元将导致脉络膜血流减少。从长远来看，我们假设视网膜将 显示外部段丢失和炎症标记的证据。我们将非侵入性评估视网膜视网膜 OCT/OCTA，LSFG和静电图（ERG）/多灶性的色素上皮和脉络膜健康。 尔格。我们将通过永久性组织学进一步评估永久性卫生验尸。提出的实验将 构成电路的第一个广泛而系统的投资，副交感神经的作用， 灵长类动物的脉络膜脉管系统中控制血流的前神经元。这些结果将设置 未来研究的阶段，该研究被调制，以改善中央视觉的生存 人黄斑变性。